Acne vulgaris is a common skin condition, most common during adolescence. It is characterized by noninflammatory follicular papules or comedones and by inflammatory papules, pustules, and nodules in its more severe forms. The areas more affected by acne are the face, the upper part of the chest, and the back. Acne lesions are commonly referred to as pimples, blemishes, spots, zits, or simply acne. In severe acne conditions, the naturally occurring bacteria Propionibacterium acnes can cause inflammation, leading to inflammatory lesions (papules, infected pustules, or nodules) in the dermis around the microcomedo or comedone, which results in redness and may result in scarring or hyperpigmentation.
Since acne affects virtually every adolescent at some point in time, the choice of therapy should be principally based on the type of lesion and the severity of the acne, but psychosocial disability relating to the disease and the presence of scarring may also influence the approach to treatment. A combination of treatments can greatly reduce the amount and severity of acne in many cases.
Benzoyl peroxide (C6H5CO)2O2, is a colorless, odorless, tasteless, crystalline solid that is stable at ordinary room temperatures but which is flammable and is capable of exploding when confined and subjected to grinding, heat or flame. It is a powerful oxidizing agent but is non-toxic to man and causes no local injurious effects and has been employed as an effective antibacterial and keratolytic agent in the treatment of acne.
Gels, creams, lotions and ointments containing the bactericide benzoyl peroxide in concentrations of 2.5%-5% and 10% are used for treatment of mild to moderate acne. In addition to its therapeutic effect as a keratolytic, benzoyl peroxide also prevents new lesions by killing P. acnes without generating bacterial resistance like antibiotics. However, benzoyl peroxide routinely causes dryness, local irritation and redness and can cause excessive skin irritation. Its poor water solubility, coupled with its chemical instability in other solvents, presents challenges with respect to formulating topical products with optimal bioavailability, stability, and tolerability. In addition, with some commercially available products in which benzoyl peroxide comprises crystals in suspension, aggregation of benzoyl peroxide can occur on the skin surface in large clumps, resulting in poor penetration into sebaceous follicles.
Many attempts have been made to provide an efficient delivery system for BPO. U.S. Pat. No. 4,056,611 discloses a therapeutic composition for the treatment of acne consisting of a stable dispersion of finely divided particles of benzoyl peroxide in an aqueous alcohol vehicle. U.S. Pat. No. 4,401,835 discloses a method for the preparation of benzoyl peroxide in crystalline form, which crystals may range in size below 10 microns, and its incorporation into cosmetic and pharmaceutical preparations. U.S. Pat. No. 6,491,953 discloses a controlled release composition comprising an adsorbent polymer, an active agent which may be benzoyl peroxide, and a release retardant, wherein the composition has an improved ability to release the active agent over an extended time period.
Methods to increase both efficacy and tolerability of benzoyl peroxide-based acne treatment have been recently reviewed (Fakhouri T, Yentzer B A, Feldman S R. Advancement in benzoyl peroxide-based acne treatment: methods to increase both efficacy and tolerability. J Drugs Dermatol. 8(7):657-61, 2009). Novel vehicles including a microparticle delivery system have been discussed in this review citing, for example, Jelvehgari et al. (2006) which disclose a microsponge delivery system of benzoyl peroxide consisting of ethyl cellulose microparticles prepared using an emulsion solvent diffusion method by adding an organic internal phase containing benzoyl peroxide, ethyl cellulose and dichloromethane into a stirred aqueous phase containing polyvinyl alcohol. The micrograph of the microsponges showed that they were spherical in shape, contained pores and had a mean particle size within a range of 230-450 μm (Jelvehgari M, Siahi-Shadbad M R, Azarmi S, Martin G P, Nokhodchi A. The microsponge delivery system of benzoyl peroxide: preparation, characterization and release studies. Int J Pharm. 308(1-2):124-32, 2006).
It would be highly desirable to provide benzoyl peroxide formulations that are stable, permit immediate release of the benzoyl peroxide to the skin and present reduced irritancy while keeping effectiveness in the treatment of acne.
U.S. Pat. No. 6,932,984 and WO 2007/023495 of the same applicant of the present application disclose a method for microencapsulation of substances by the solvent removal method using non-chlorinated solvents. The method is based on physical processes only which do not cause any change of original physical and/or chemical properties, biological activity, and safety of raw materials during the process. This method affords physical stability of the microcapsules during the preparation of the formulation, high ability to entrap the active agents, protection of the active agents inside the microcapsules, prevention of the diffusion of the microencapsulated active agents to the external water phase in a water-based preparation, and optimal controlled release only upon application to the skin.